Tumor development is associated with major metabolic changes. In the 1920s, Otto Warburg observed that cancer cells have high glucose consumption and lactate production even in the presence of oxygen (a process termed aerobic glycolysis). Recent research has demonstrated that these metabolic differences drive tumor growth. By modulating their metabolic processes, cancer cells are able to divert sugars, fats and other energy sources away from energy production to satisfy the ever growing demands of uncontrolled proliferation.
Pyruvate Kinase (PK) is a metabolic enzyme that catalyzes the transfer of a phosphate group from phosphoenol pyruvate to ADP, to produce pyruvate and ATP during glycolysis. There are four PK isozymes—the L and the R isozymes are expressed in liver and red blood cells, respectively; the M1 isozyme is expressed in most adult cells, and the M2 isoenzyme—an M2 splice variant (PKM2)—is exclusively expressed during embryonic development and in cancer cells.
While PKM1 is a constitutively active enzyme, PKM2 undergoes a transformation from an energy efficient tetrametic form to an ‘energy inefficient’ dither form. The main effector that balances the dimer-tetramer ratio of PKM2 in tissues is fructose 1,6-bisphosphate (FBP), a glycolysis intermediate product upstream of PKM2.
PKM2 is a key mediator of the Warburg effect in cancer cells leading to lower energy production and an abundance of building blocks for tumor replication and growth. There is thus a need in the art for, inter alia, modulators of the metabolism of proliferating cells.